A Life-Course Approach to Assessing Effects of Environmental Exposures on Kidney Development

Project Summary NYU Grossman School of Medicine and Erasmus University Medical Center jointly propose to evaluate how organophosphate pesticides, glyphosate, phthalates and bisphenols contribute to renal risks in childhood and adolescence. The incidence of chronic kidney disease (CKD) is steadily rising and synthetic chemicals are increasingly understood to contribute to acute and chronic kidney injury. Case-control studies of populations with high incidence rates have identified pesticide and herbicide exposures as risks, raising the question whether developmental exposures may be even more impactful. Our own studies of children with CKD (R01DK100307) have revealed modest declines in kidney function with increasing phthalate and bisphenol exposures, accompanied by increases in oxidative stress. However, these findings do not contribute to our understanding of the origin of CKD. A major limitation is the failure of our and other studies to account for the developmental biology of the kidney and strong influence of perinatal/infant factors. The premise of the present proposal is that intrauterine inflammatory processes disrupt nephrogenesis and that environmental chemicals also impair renal parenchymal growth longitudinally during gestation and postnatal development via oxidant stress. We further interrogate this hypothesis by examining phthalates, bisphenols, glyphosate and organophosphate (OP) pesticides as modifiable risks. We will test these hypotheses in Generation R First, a prospective, longitudinal multi-ethnic birth cohort with existing measurements of phthalate and bisphenol exposure at three time points in pregnancy and three time points in childhood (5-6, 9-10 and 13-14 years) in 1405 mother-infant pairs (funded by R01ES022972 and R01ES032826). Organophosphate (OP) exposures were measured in the same time points in pregnancy in a subsample of 776 (ZIAES103314). We therefore propose to: add measurements of glyphosate and oxidative stress exposure in pregnancy and childhood at the same six time points (n=1312 children with at least one measure of kidney size, eGFR or albuminuria); complete the measurements of OP in pregnancy and childhood to permit mixture analyses that also consider phthalates, bisphenols and glyphosate; and evaluate glomerular (albuminuria) and tubular injury (KIM-1, NGAL) as well as functional renal mass (urinary epidermal growth factor, EGF) at the four time points in childhood. Leveraging Generation R First for the proposed work presents substantial cost-efficiency, with available measurements of kidney size, eGFR and albuminuria at ages 5-6, 9-10 and 13-14, and planned measurements at 17-18 years of age. The proposal couples the expertise of an internationally renowned environmental pediatrician (Trasande) with a life course epidemiologist (Jaddoe) who is PI of Generation R.